The present invention relates to the use of microwave assisted techniques to carry out chemical reactions, particularly sophisticated chemical synthesis reactions. More specifically, the invention relates to an apparatus and method for controlled pressure release during such synthesis in a microwave-assisted instrument.
The present invention is related to and commonly-assigned application Ser. No. 09/773,846 filed Jan. 31, 2001, and now U.S. Pat. No. 6,753,517 by Jennings for Microwave-Assisted Chemical Synthesis Instrument With Fixed Tuning, the contents of which are incorporated entirely herein by reference (“the '846 application”).
As set forth in the '846 application, interest has grown in the use of microwave assisted techniques for chemical synthesis, particularly organic synthesis using relatively small amounts of reagents. The term “small” is used herein in a relative sense, but those familiar with modern experimental synthesis techniques such as the development of pharmaceuticals recognize that sample sizes of 5 milliliters (ml) or less are quite common, particularly when numerous sample reactions are being studied. In recent years, the availability and lowered cost of computer processing power and memory has given rise in the areas of chemical synthesis and analysis to automated and semi-automated techniques that carry out such chemical processes in relatively rapid fashion on large numbers of such small samples, and that quickly provide useful information based on the completed processes. Thus, the potential to include microwave assistance as a part of such processes offers another method of increasing the speed with which they can be carried out, and thus correspondingly increase the number of processes that can be carried out within any given time frame.
The use of small amounts raises different problems than have traditionally been raised in other areas of microwave-assisted chemistry such as digestion and loss-on-drying moisture content determinations. Such prior (and still extremely useful) microwave assisted techniques and instruments have now been joined by this newer generation of sophisticated microwave assisted instruments that can focus microwave energy on very small samples in a manner that heats the samples in a desired and controlled manner without overheating them or driving the reagents to decomposition. By way of comparison, complete or near-complete decomposition is the goal of digestion, and thus excessive (relatively speaking) temperatures generally represent less of a process problem. Chemical synthesis, however, has the goal of encouraging particular reactants to act in an expected or predictable manner to produce desired products. Thus, in many synthesis scenarios temperature and pressure (among other factors) must be maintained within appropriate limits.
In addition to the '846 application, other recent advances in microwave assisted chemistry include (but are not limited to) those discussed in U.S. Pat. Nos. 6,320,170; 6,302,577; 6,268,570; 6,227,041; 5,796,080.
The '846 application discloses an instrument that can handle relatively small samples, typically liquid samples of organic materials, and that can apply precise and moderated amounts of microwave energy within its cavity to drive reactions carried out in vessels in the cavity in a manner appropriate to chemical synthesis. In particular, the '846 application discloses a sophisticated structure for measuring the pressure inside of sealed vessels while reactions are proceeding. As known to those familiar with chemical synthesis, particularly in closed conditions, the pressure generated can be a measure of several factors, the primary ones typically being gaseous byproducts from the reaction, or an increase in gas temperature in accordance with the ideal gas laws, or both. Accordingly, pressure measurement is a valuable option in such instruments. In the '846 application, a reaction vessel, one version of which resembles a classic test tube, is sealed in a pressure-resistant manner with a metal cap and a flexible septum. A small needle is positioned to pierce and penetrate the septum, and is in fluid (usually gas) communication with a pressure transducer at the needle's opposite end. Using the instrument, the pressure inside of the vessel can be constantly monitored as a reaction proceeds and as microwave energy is applied.
In the instrument described in the '846 application, however, the only way to release pressure inside the reaction vessel is to remove the cap completely from the vessel (e.g. at the completion of a desired reaction) or alternatively to remove the transducer from the needle. In one case the reaction may be affected or interrupted, while in the other the ability to measure pressure is forfeited.
Furthermore, the instrument described in the '846 application lacks any convenient means for attaching the vessel to a gas source, should that be desired or required in particular circumstance.
Thus, although this is satisfactory in a number of circumstances, and although the instrument described in the '846 application is a significant improvement in microwave-assisted synthesis techniques and instrumentation, and has gained rapid commercial acceptance, the need still exists for an apparatus in which pressure can be controllably released (bled or vented) from a reaction vessel—or a gas added thereto—as the reaction proceeds. Such potential release offers several advantages, such as the ability to keep pressure below a certain threshold, or to drive a reaction towards completion by removing one of the reaction products from the environment in accordance with LeChatelier's principle. In this regard, gases are the products of certain reactions, and absent the capability to release or relieve the associated increase in pressure in a closed environment, the reactions must be avoided in order to avoid pressure-related failure of the vessel.
In another aspect, lack of controlled communication with a closed vessel can prevent the use of additional reagents, such as adding liquids or gases (as solvents or reagents) in order to carry out a later stage of a multi-step reaction.
Pressure-release vessels exist for microwave assisted chemistry, but generally in the context of preventing a pressure generated failure that renders the vessel unusable. For example, in commonly assigned U.S. Pat. Nos. 5,230,865 and 5,369,034 pressure release is provided by a disposable polymeric barrier (e.g. a rupture disk) positioned to block one of the gas passageways between the pressurized interior of the reaction vessel and its lower-pressure (often atmospheric) surroundings. When the pressure inside the vessel exceeds the threshold of the barrier (which should be selected to be less than that of the remainder of the vessel), the barrier fails and the interior pressure is released. Although such pressure release is “controlled” in the sense that it prevents total failure of the vessel, it is uncontrolled in the sense that the pressure cannot be monitored and adjusted as a reaction in the vessel proceeds.
The '034 and '865 patents also include a pressure bleed capability, but not in conjunction with pressure measurement.
Commonly assigned U.S. Pat. No. 6,086,826 shows a different type of pressure measurement in which a pressure transducer is mounted outside of a closed vessel and the movement of the exterior of the vessel against the transducer gives a representative measurement of the pressure inside the vessel. This provides specific advantages when the pressure measurement device is best isolated from the reaction in the vessel, for example under particularly harsh chemical conditions such as digestion. It does not, however, provide the more convenient temperature monitoring and control useful, and sometimes necessary, in synthesis of small samples in more carefully controlled reactions.
Several patents to Floyd, including U.S. Pat. Nos. 4,904,450; 5,204,065 and 5,264,185 also include a rupture-disk type of pressure relief system. The Floyd '185 patent also includes a transducer, but the rupture disk is positioned as a diaphragm between the vessel and the transducer; i.e. there exist no direct fluid communication unless and until the rupture disks breaks under pressure. Thus pressure can only be measured in a secondary fashion, and provided the limits of the ruptured disk are not exceeded.
Lautenschlager No. 5,725,835 discloses a device in which a gas (fluid) path extends from a reaction chamber to a series of valves, one of which is electrically controlled, one of which is spring biased, one of which is a simple rupture disk, and one of which operates manually. As set forth in FIG. 2 and the related discussion in the '835 patent, however, such pressure control is carried out between the reaction chamber and the valves rather than between individual vessels and the valves.
Strauss U.S. Pat. No. 5,932,075 illustrates a vessel having a closure or cover that carries a number of control items, including a pressure measurement path, a separate pressure release path independent of the pressure measurement path, a sampling path, and a temperature measurement device, the key feature of which, according to Strauss, is the use of a heat exchanger (24 in several of the Strauss figures) that permits a reaction to be heated or cooled while in progress. The Strauss device and its cover require a fair degree of complexity, however, and is potentially less conducive for repetitive use on larger numbers of small samples.
Furthermore, other than the '846 application, none of these devices provides a practical structure or method for quickly carrying out numerous reactions in sequential fashion. Stated differently, none provide a method or apparatus wherein reagents can be added to a number of vessels following which the vessels can be sealed and placed in a microwave cavity, can have the pressure and temperature therein measured while microwaves are being applied, and can be removed from the cavity, all without opening the vessel or fatally breaching the seal.
Accordingly, the need exists for apparatus and related techniques that can carry out microwave-assisted synthesis on small samples while still providing the opportunity desired for controlled pressure release, including pressure release during ongoing reactions.